The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein

Research output: Contribution to journalArticle

Muhan Chen, Dawid G. Nowak, Navneet Narula, Brian Robinson, Kaitlin Watrud, Alexandra Ambrico, Tali M. Herzka, Martha E. Zeeman, Matthias Minderer, Wu Zheng, Saya H. Ebbesen, Kendra S. Plafker, Carlos Stahlhut, Victoria M.Y. Wang, Lorna Wills, Abu Nasar, Mireia Castillo-Martin, Carlos Cordon-Cardo, John E. Wilkinson, Scott Powers & 6 others Raffaella Sordella, Nasser K. Altorki, Vivek Mittal, Brendon M. Stiles, Scott M. Plafker, Lloyd C. Trotman

Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

Original languageEnglish (US)
Pages (from-to)641-656
Number of pages16
JournalThe Journal of cell biology
Volume216
Issue number3
DOIs
StatePublished - Mar 6 2017

PMID: 28193700

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The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. / Chen, Muhan; Nowak, Dawid G.; Narula, Navneet; Robinson, Brian; Watrud, Kaitlin; Ambrico, Alexandra; Herzka, Tali M.; Zeeman, Martha E.; Minderer, Matthias; Zheng, Wu; Ebbesen, Saya H.; Plafker, Kendra S.; Stahlhut, Carlos; Wang, Victoria M.Y.; Wills, Lorna; Nasar, Abu; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Wilkinson, John E.; Powers, Scott; Sordella, Raffaella; Altorki, Nasser K.; Mittal, Vivek; Stiles, Brendon M.; Plafker, Scott M.; Trotman, Lloyd C.

In: The Journal of cell biology, Vol. 216, No. 3, 06.03.2017, p. 641-656.

Research output: Contribution to journalArticle

Harvard

Chen, M, Nowak, DG, Narula, N, Robinson, B, Watrud, K, Ambrico, A, Herzka, TM, Zeeman, ME, Minderer, M, Zheng, W, Ebbesen, SH, Plafker, KS, Stahlhut, C, Wang, VMY, Wills, L, Nasar, A, Castillo-Martin, M, Cordon-Cardo, C, Wilkinson, JE, Powers, S, Sordella, R, Altorki, NK, Mittal, V, Stiles, BM, Plafker, SM & Trotman, LC 2017, 'The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein' The Journal of cell biology, vol. 216, no. 3, pp. 641-656. https://doi.org/10.1083/jcb.201604025

APA

Chen, M., Nowak, D. G., Narula, N., Robinson, B., Watrud, K., Ambrico, A., ... Trotman, L. C. (2017). The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. The Journal of cell biology, 216(3), 641-656. https://doi.org/10.1083/jcb.201604025

Vancouver

Chen M, Nowak DG, Narula N, Robinson B, Watrud K, Ambrico A et al. The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. The Journal of cell biology. 2017 Mar 6;216(3):641-656. https://doi.org/10.1083/jcb.201604025

Author

Chen, Muhan ; Nowak, Dawid G. ; Narula, Navneet ; Robinson, Brian ; Watrud, Kaitlin ; Ambrico, Alexandra ; Herzka, Tali M. ; Zeeman, Martha E. ; Minderer, Matthias ; Zheng, Wu ; Ebbesen, Saya H. ; Plafker, Kendra S. ; Stahlhut, Carlos ; Wang, Victoria M.Y. ; Wills, Lorna ; Nasar, Abu ; Castillo-Martin, Mireia ; Cordon-Cardo, Carlos ; Wilkinson, John E. ; Powers, Scott ; Sordella, Raffaella ; Altorki, Nasser K. ; Mittal, Vivek ; Stiles, Brendon M. ; Plafker, Scott M. ; Trotman, Lloyd C. / The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. In: The Journal of cell biology. 2017 ; Vol. 216, No. 3. pp. 641-656.

BibTeX

@article{1ccebe4a6d024666a58afa6587a0c180,
title = "The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein",
abstract = "Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.",
author = "Muhan Chen and Nowak, {Dawid G.} and Navneet Narula and Brian Robinson and Kaitlin Watrud and Alexandra Ambrico and Herzka, {Tali M.} and Zeeman, {Martha E.} and Matthias Minderer and Wu Zheng and Ebbesen, {Saya H.} and Plafker, {Kendra S.} and Carlos Stahlhut and Wang, {Victoria M.Y.} and Lorna Wills and Abu Nasar and Mireia Castillo-Martin and Carlos Cordon-Cardo and Wilkinson, {John E.} and Scott Powers and Raffaella Sordella and Altorki, {Nasser K.} and Vivek Mittal and Stiles, {Brendon M.} and Plafker, {Scott M.} and Trotman, {Lloyd C.}",
year = "2017",
month = "3",
day = "6",
doi = "10.1083/jcb.201604025",
language = "English (US)",
volume = "216",
pages = "641--656",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "3",

}

RIS

TY - JOUR

T1 - The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein

AU - Chen, Muhan

AU - Nowak, Dawid G.

AU - Narula, Navneet

AU - Robinson, Brian

AU - Watrud, Kaitlin

AU - Ambrico, Alexandra

AU - Herzka, Tali M.

AU - Zeeman, Martha E.

AU - Minderer, Matthias

AU - Zheng, Wu

AU - Ebbesen, Saya H.

AU - Plafker, Kendra S.

AU - Stahlhut, Carlos

AU - Wang, Victoria M.Y.

AU - Wills, Lorna

AU - Nasar, Abu

AU - Castillo-Martin, Mireia

AU - Cordon-Cardo, Carlos

AU - Wilkinson, John E.

AU - Powers, Scott

AU - Sordella, Raffaella

AU - Altorki, Nasser K.

AU - Mittal, Vivek

AU - Stiles, Brendon M.

AU - Plafker, Scott M.

AU - Trotman, Lloyd C.

PY - 2017/3/6

Y1 - 2017/3/6

N2 - Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

AB - Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

UR - http://www.scopus.com/inward/record.url?scp=85021848032&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021848032&partnerID=8YFLogxK

U2 - 10.1083/jcb.201604025

DO - 10.1083/jcb.201604025

M3 - Article

VL - 216

SP - 641

EP - 656

JO - Journal of Cell Biology

T2 - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 3

ER -

ID: 38716922